CN105541834B - A kind of synthetic method of 2 phenylimidazoles simultaneously [1,2 a] pyridine compounds and their - Google Patents
A kind of synthetic method of 2 phenylimidazoles simultaneously [1,2 a] pyridine compounds and their Download PDFInfo
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- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical class C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 150000004941 2-phenylimidazoles Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 230000010355 oscillation Effects 0.000 claims abstract description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 7
- 238000000498 ball milling Methods 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 239000005864 Sulphur Substances 0.000 claims 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 3
- 238000000227 grinding Methods 0.000 abstract description 2
- ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 2-phenyl-1h-imidazole Chemical compound C1=CNC(C=2C=CC=CC=2)=N1 ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 description 6
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 6
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- VSLIUWLPFRVCDL-UHFFFAOYSA-N zolimidine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 VSLIUWLPFRVCDL-UHFFFAOYSA-N 0.000 description 4
- 229960003118 zolimidine Drugs 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 102000027484 GABAA receptors Human genes 0.000 description 2
- 108091008681 GABAA receptors Proteins 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 description 1
- 108700036626 Melanin-concentrating hormone receptor 1 Proteins 0.000 description 1
- BHGNTIYYEFHIQN-UHFFFAOYSA-N N1=CC=CC=C1.N1=CCN2C1=CC=C2 Chemical compound N1=CC=CC=C1.N1=CCN2C1=CC=C2 BHGNTIYYEFHIQN-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- QUDMHFVRKBVGBY-FQEVSTJZSA-N [5-(4-methylpiperazin-1-yl)-2-[[methyl-[(8s)-5,6,7,8-tetrahydroquinolin-8-yl]amino]methyl]imidazo[1,2-a]pyridin-3-yl]methanol Chemical compound CN([C@@H]1C2=NC=CC=C2CCC1)CC(=C(N12)CO)N=C1C=CC=C2N1CCN(C)CC1 QUDMHFVRKBVGBY-FQEVSTJZSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- JRTIDHTUMYMPRU-UHFFFAOYSA-N alpidem Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N(CCC)CCC)=C1C1=CC=C(Cl)C=C1 JRTIDHTUMYMPRU-UHFFFAOYSA-N 0.000 description 1
- 229950008673 alpidem Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000884 anti-protozoa Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 1
- 229950011129 minodronic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 description 1
- 229950005421 olprinone Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000009527 percussion Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of 2 phenylimidazole simultaneously [1,2 a] pyridine compounds and their, compared with prior art, present invention synthesis uses high frequency machinery grinding technique, and one step of reaction is completed, simple to operate；And without using solvent in course of reaction, the big chemical reagent of toxicity is not related to, the reaction time is short, reaction can be completed in 90 minutes, reaction condition is gentle, is reacted at room temperature with 30Hz frequency of oscillation, and yield is high, can obtain up to 94% yield；And this method can quickly be effectively synthesized out simultaneously [1, the 2 a] pyridine of 2 phenylimidazoles with strong electron-withdrawing group group, and this class product conventional method is difficult to be synthesized or yield is very low, unless using very extreme and harsh reaction condition.
Description
Technical field
The invention belongs to organic synthesis field, and in particular to a kind of 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their
Synthetic method.
Background technology
In many nitrogenous condensed ring azoles, imidazo [1,2-a] pyridine is because it is in many aspects such as pharmaceutical chemistry, You Jijin
Belong to the extensive use in the field such as compound and material science and play very important effect.Although imidazo [1,2-a] pyrrole
Pyridine and Benzodiazepine are different in structure, but their pharmacological property is but very similar with benzodiazepine,
Therefore they are referred to as non-Benzodiazepine.
Molecule containing imidazo [1,2-a] pyridine structure has extensive bioactivity, for example：Antimycotic, antiviral,
Antibacterial, anticancer, antiprotozoan, anti-inflammatory, anticonvulsion, antipyretic, expelling parasite, analgesic, anti-epileptic, antituberculosis, antiulcer, selective hypnosis
With selective antianxiety.They are equally used as GABAA receptor stimulating agents, 5- lipoxidase inhibitors, cyclic protein dependent kinase
Enzyme inhibitor, MCH1R antagonists, part, HIF-1 α prolyl hydroxylase inhibitors and the histamine H of beta-amyloyd detection2Acceptor
Antagonist and be widely studied.
Also imidazo [1,2-a] pyridine structure is contained among many commercial pharmaceuticals.These commercial pharmaceuticals include：Alpidem and
Zolpidem (be used for treat anxiety and insomnia), husky vertical pyrrole is smooth and naphthalene can pyrrole smooth (anxiolytic drugs), Olprinone (cardiotonic), miaow
Ibuprofen (anodyne), DS-1 (GABAA receptor stimulating agents), zolimidine (being used to treat digestive tract ulcer), GSK812397 (are controlled
Treat the drug candidate of HIV) and minodronic acid (being used to treat osteoporosis).
Because imidazo [1,2-a] pyridine has a wide range of applications in many fields, therefore it have also been developed many synthesis
Their method.Particularly last decade synthesized by using multicomponent, the c h bond function dough of cascade reaction and transition metal it is anti-
Some novel method for synthesizing and synthesis theory should be waited so that the synthesis of imidazo [1,2-a] pyridine is significantly developed.But this
The larger isonitrile of the use strong and stimulating and corrosive phenacyl bromide that have in a little synthetic methods, the use toxicity having
For reactant, some need oxygen to be aoxidized, some need to use noble metal or heavy metal and part are participated in, the bar of reaction
Part is harsher.
In synthetic method recited above, reaction is needed to complete in organic solvent, and heating, reaction are needed in course of reaction
Time is long, using the chemical reagent that toxicity is larger, and product isolate and purify it is comparatively laborious.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of conjunction of 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their
Into method, without heating, without solvent, mild condition, the reaction time is short and simple to operate, can quickly be effectively synthesized out some biographies
Several 2- phenylimidazoles rolled into a ball with strong electron-withdrawing group that system method is difficult to be synthesized simultaneously [1,2-a] pyridine compounds and their.
A kind of synthetic method of 2- phenylimidazoles that the present invention is provided simultaneously [1,2-a] pyridine compounds and their, including following step
Suddenly：
(a), willIodine and DMAP are placed in mechanico-chemical reaction tank, vibration
Ball-milling reaction；
(b) after, reaction terminates, product is washed, extract, dry, filtered, filtrate separates after being evaporated through silica gel column chromatography,
Obtain 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their.
Reaction equation is：
In step (a)The mol ratio of iodine and DMAP is 1.2~1.5:1:1
~1.2:1.
It is describedR1For H or 4- methyl；It is describedR2For H, 2-Br, 3-Br, 4-Br, 3-NO2、4-
NO2、4-SO2Me or 4-OCH3。
Mechanico-chemical reaction device described in step (a) is that German Lay is speeded mechanico-chemical reaction device (MM400).
Vibration ball-milling reaction condition described in step (a) is：Frequency of oscillation be 25~30Hz, the reaction time be 90~
120 minutes.
Washing described in step (b) uses sodium thiosulfate solution to wash；Sodium thiosulfate solution it is dense
Spend for 1.0mol/L.
The extractant used in step (b) is volume ratio 1:1 ethyl acetate and the mixed liquor of water.
Further, the drier used in step (b) is anhydrous magnesium sulfate；
The structural formula of products therefrom 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their is：
R1For H or 4- methyl；R2For H, 2-Br, 3-Br, 4-Br, 3-NO2、4-NO2、4-SO2Me or 4-OCH3。
Compared with prior art, simultaneously the synthesis of [1,2-a] pyridine uses high frequency machinery grinding technique to 2- phenylimidazoles of the present invention,
Step completion is reacted, it is simple to operate；And without using solvent in course of reaction, the big chemical reagent of toxicity, reaction time are not related to
It is short, reaction can be completed in 90~120 minutes, reaction condition is gentle, is carried out at room temperature with 25~30Hz frequency of oscillation
Solvent-free high frequency ball-milling reaction, and yield is high, can obtain 94% yield；Enter due to reacting under high frequency ball milling condition
OK, reaction produces heat, and therefore, inside reaction kit, temperature can reach 40-45 DEG C.And this method quickly can be closed effectively
Into the 2- phenylimidazoles for going out that conventional method can not synthesize and rolling into a ball with strong electron-withdrawing group simultaneously [1,2-a] pyridine, and this class product
Conventional method is difficult to be synthesized or yield is very low, unless using very extreme and harsh reaction condition.The present invention is adopted
The mechanical chemical technique of high frequency ball milling, due in course of reaction without using solvent, the reaction raw materials local concentration provided
It is high；And the friction that is produced in the technical process, shearing, percussion can induce some low activity reactants in normal condition
Under be difficult to or even the reaction that can not carry out, so roll into a ball the active relatively low acetophenone of substitution for some strong electron-withdrawing groups,
Preferable yield can be obtained.
Figure of description
Fig. 1 is the proton nmr spectra of 2- phenylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 11H-NMR schemes；
Fig. 2 is the carbon-13 nmr spectra of 2- phenylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 113C-NMR schemes；
Fig. 3 is the proton nmr spectra of 2- (2- bromophenyls) imidazo [1,2-a] pyridine prepared by embodiment 21H-NMR
Figure；
Fig. 4 is the carbon-13 nmr spectra of 2- (2- bromophenyls) imidazo [1,2-a] pyridine prepared by embodiment 213C-NMR
Figure；
Fig. 5 is the proton nmr spectra of 2- (4- bromophenyls) imidazo [1,2-a] pyridine prepared by embodiment 31H-NMR
Figure；
Fig. 6 is the carbon-13 nmr spectra of 2- (4- bromophenyls) imidazo [1,2-a] pyridine prepared by embodiment 313C-NMR
Figure；
Fig. 7 is the proton nmr spectra of 2- (3- nitrobenzophenones) imidazo [1,2-a] pyridine prepared by embodiment 41H-NMR
Figure；
Fig. 8 is the carbon-13 nmr spectra of 2- (3- nitrobenzophenones) imidazo [1,2-a] pyridine prepared by embodiment 413C-NMR
Figure；
Fig. 9 is the proton nmr spectra of 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine prepared by embodiment 51H-NMR
Figure；
Figure 10 is the carbon-13 nmr spectra of 2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine prepared by embodiment 513C-
NMR schemes；
Figure 11 is the nuclear-magnetism of 2- (4- methylsulfonyls phenyl) imidazo [1,2-a] pyridine (zolimidine) prepared by embodiment 6
Resonate hydrogen spectrum1H-NMR schemes；
Figure 12 is the nuclear-magnetism of 2- (4- methylsulfonyls phenyl) imidazo [1,2-a] pyridine (zolimidine) prepared by embodiment 6
Resonate carbon spectrum13C-NMR schemes；
Figure 13 is the proton nmr spectra of 2- phenyl -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 71H-NMR
Figure；
Figure 14 is the carbon-13 nmr spectra of 2- phenyl -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 713C-NMR
Figure；
Figure 15 is the hydrogen nuclear magnetic resonance of 2- (2- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 8
Spectrum1H-NMR schemes；
Figure 16 is the nuclear magnetic resonance carbon of 2- (2- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 8
Spectrum13C-NMR schemes；
Figure 17 is the hydrogen nuclear magnetic resonance of 2- (4- anisyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 9
Spectrum1H-NMR schemes；
Figure 18 is the nuclear magnetic resonance carbon of 2- (4- anisyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 9
Spectrum13C-NMR schemes；
Figure 19 is the nuclear magnetic resonance of 2- (3- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 10
Hydrogen is composed1H-NMR schemes；
Figure 20 is the nuclear magnetic resonance of 2- (3- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 10
Carbon is composed13C-NMR schemes；
Figure 21 is the nuclear magnetic resonance of 2- (4- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 11
Hydrogen is composed1H-NMR schemes；
Figure 22 is the nuclear magnetic resonance of 2- (4- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 11
Carbon is composed13C-NMR schemes；
Figure 23 is the hydrogen nuclear magnetic resonance of 2- (4- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 12
Spectrum1H-NMR schemes；
Figure 24 is the nuclear magnetic resonance carbon of 2- (4- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine prepared by embodiment 12
Spectrum13C-NMR schemes.
Embodiment
Embodiment 1
A kind of synthetic method of 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their, comprises the following steps：
Weigh 1.41 grams of (15 mMs) PAs, 1.2 grams of (10 mMs) acetophenones, 2.54 grams (10 mMs)
Iodine and 1.22 grams of (10 mMs) DMAPs, are placed in one 25 milliliters of mechanico-chemical reaction tank, it is parallel feed intake in
In another same mechanico-chemical reaction tank, German Lay is fixed on after screwing hermetic and is speeded the Swing Arm of mechanico-chemical reaction device
On.Reacted 90 minutes under 30Hz frequency of oscillation.After question response terminates, the reactant mixture volume ratio 1 of two tanks:1 second
Acetoacetic ester and water mixed liquid extraction, merge and collect ethyl acetate phase and filtered after being dried through anhydrous magnesium sulfate, filtrate passes through after being evaporated
Silica gel column chromatography separates (eluant, eluent：V petroleum ethers/V ethyl acetate=3:1) 1.74 grams of 2- phenylimidazoles simultaneously [1,2-a] pyridine is obtained
Sterling, state is white solid, and yield is 90%.
Embodiment 2-12
2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their is prepared using different raw material, experimental implementation be the same as Example 1,
Specifically used raw material and product, see the table below 1；Reaction condition control is specifically shown in table 2 below.
Table 1
*Note：DMAP is 4-lutidines
Table 2
The nuclear magnetic resoance spectrum of the product of embodiment 1-12 is as follows：
Embodiment 1：2- phenylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.12 (d, J=7.0Hz, 1H, ArH), 7.96 (d, J=8.0Hz, 2H, ArH),
7.86 (s, 1H, ArH), 7.66 (d, J=9.0Hz, 1H, ArH), 7.44 (t, J=7.75Hz, 2H, ArH), 7.33 (t, J=
7.3Hz, 1H, ArH), 7.18 (t, J=7.75Hz, 1H, ArH), 6.79 (t, J=6.75Hz, 1H, ArH)；13C NMR
(125MHz,CDCl3)δ146.2,146.1,134.2,129.1,128.4,126.5,126.0,125.0,118.0,112.8,
108.5.
Embodiment 2：2- (2- bromophenyls) imidazo [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.28 (s, 1H, ArH), 8.15 (t, J=7.8Hz, 2H, ArH), 7.66 (dd, J
=8.0,0.5Hz, 1H, ArH), 7.63 (d, J=9.0Hz, 1H, ArH), 7.41 (td, J=7.75,1.0Hz, 1H, ArH),
7.17 (td, J=7.13,1.5Hz, 2H, ArH), 6.78 (td, J=6.75,0.75Hz, 1H, ArH)；13C NMR(125MHz,
CDCl3)δ144.9,143.5,134.8,134.1,132.1,129.3,128.0,126.2,125.2,121.9,118.0,
112.9,112.4.
Embodiment 3：2- (4- bromophenyls) imidazo [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.08 (d), 7.83 (t, J=6.8Hz, 3H, ArH), 7.62 (d, J=9.0Hz,
1H, ArH), 7.55 (d, J=8.5Hz, 2H, ArH), 7.18 (t, J=7.8Hz, 1H, ArH), 6.78 (t, J=6.8Hz, 1H,
ArH)；13C NMR(125MHz,CDCl3)145.7,144.7,132.8 131.8,127.6 125.6,124.9,121.9,
117.6,112.6,108.2.
Embodiment 4：2- (3- nitrobenzophenones) imidazo [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.75 (s, 1H, ArH), 8.35 (d, J=8.5Hz, 1H, ArH), 8.17 (dd, J
=8.0,1.0Hz, 2H, ArH), 7.99 (s, 1H, ArH), 7.67 (d, J=9.0Hz, 1H, ArH), 7.61 (t, J=8.0Hz,
1H, ArH), 7.25 (dd, J=6.0,1.0Hz, 1H, ArH), 6.85 (td, J=6.75,0.5Hz, 1H, ArH)；13C NMR
(125MHz,CDCl3)δ149.2,146.3,143.9,136.1,132.2,130.1,126.2,125.8,122.9,121.2,
118.2,113.4,109.4.
Embodiment 5：2- (4- nitrobenzophenones) imidazo [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.31 (d, J=9.0Hz, 2H, ArH), 8.17 (dt, J=7.0,1.0Hz, 1H,
), ArH 8.13 (d, J=9.0Hz, 2H, ArH), 8.01 (s, 1H, ArH), 7.67 (dd, J=9.1,0.8Hz, 1H, ArH),
7.24-7.27 (m, 1H, ArH), 6.86 (td, J=6.8,1.1Hz, 1H, ArH)；13C NMR(125MHz,CDCl3)δ147.3,
146.1,143.4,140.2,126.5,125.8,125.7,124.2,118.0,113.2,109.9.
Embodiment 6：2- (4- methylsulfonyls phenyl) imidazo [1,2-a] pyridine (zolimidine)
1H NMR(500MHz,CDCl3) δ 8.15 (d, J=7.5Hz, 2H, ArH), 8.12 (d, J=1.5Hz, 1H, ArH),
7.99 (d, J=1.5Hz, 1H, ArH), 7.97 (s, 2H, ArH), 7.64 (d, J=9.1Hz, 1H, ArH), 7.22 (ddd, J=
9.1,6.8,1.2Hz, 1H, ArH), 6.82 (td, J=6.8,1.0Hz, 1H, ArH), 3.09 (s, 3H, CH3)；13C NMR
(125MHz,CDCl3)δ146.0,143.6,139.3,139.2,127.9,126.6,125.8,125.5,117.8,113.0,
109.7,44.6.
Embodiment 7：2- phenyl -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 7.99 (d, J=7.5Hz, 1H, ArH), 7.94 (d, J=8.0Hz, 2H, ArH),
7.77 (s, 1H, ArH), 7.43 (d, J=7.5Hz, 1H, ArH), 7.40 (d, J=7.0Hz, 1H, ArH), 7.31 (t, J=
7.5Hz, 1H, ArH), 6.60 (dd, J=6.5,1.0Hz, 1H, ArH), 2.39 (s, 3H, CH3)；13C NMR(125MHz,
CDCl3)δ146.5,145.9,135.9,134.3,129.0,128.2,126.4,125.2,116.3,115.4,107.9,
21.7.
Embodiment 8：2- (2- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.15 (s, 2H, ArH), 8.13 (dd, J=7.8,1.8Hz, 1H, ArH), 7.93
(d, J=6.9Hz, 1H, ArH), 7.63 (dd, J=8.0,1.1Hz, 1H, ArH), 7.37 (td, J=7.5,1.0Hz, 2H,
ArH), 7.34 (s, 1H, ArH), 7.13 (td, J=7.9,1.8Hz, 1H, ArH), 6.54 (dd, J=6.5,1.5Hz, 1H,
ArH),2.34(s,3H,CH3)；13C NMR(125MHz,CDCl3)δ144.8,142.7,135.7,134.4,133.5,131.4,
128.6,127.4,124.8,121.3,115.6,115.0,111.3,21.2.
Embodiment 9：2- (4- anisyls) -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 7.97 (d, J=6.8Hz, 1H, ArH), 7.87 (d, J=8.7Hz, 2H, ArH),
7.69 (s, 1H, ArH), 7.37 (s, 1H, ArH), 6.97 (d, J=8.8Hz, 2H, ArH), 6.59 (d, J=6.8Hz, 1H,
ArH),3.85(s,3H,OCH3),2.39(s,3H,CH3)；13C NMR(125MHz,CDCl3)δ159.8,146.4,145.7,
135.8,127.6,127.0,125.1,116.0,115.2,114.5,107.0,55.7,21.7.
Embodiment 10：2- (3- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.72 (s, 1H, ArH), 8.29 (dd, J=8.0,1.0Hz, 1H, ArH), 8.13
(dd, J=8.25,1.0Hz, 1H, ArH), 8.01 (d, J=7.0Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.57 (t, J=
8.0Hz, 1H, ArH), 7.38 (s, 1H, ArH), 6.65 (dd, J=7.0,1.5Hz, 1H, ArH), 2.4 (s, 3H, CH3)；13C
NMR(125MHz,CDCl3)δ149.0,146.7,143.5,136.9,136.3,132.1,130.0,125.4,122.6,
121.0,116.4,116.0,108.9,21.8.
Embodiment 11：2- (4- nitrobenzophenones) -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 8.27 (d, J=9.0Hz, 2H, ArH), 8.07 (d, J=9.0Hz, 2H, ArH),
8.02 (d, J=6.9Hz, 1H, ArH), 7.90 (s, 1H, ArH), 7.40 (s, 1H, ArH), 6.67 (dd, J=6.9,1.5Hz,
1H,ArH),2.42(s,3H,CH3)；13C NMR(125MHz,CDCl3)δ147.1,146.6,143.1,140.4,136.7,
126.3,125.0,124.1,116.2,115.9,109.4,21.4.
Embodiment 12：2- (4- bromophenyls) -7- methylimidazoles simultaneously [1,2-a] pyridine
1H NMR(500MHz,CDCl3) δ 7.96 (d, J=6.9Hz, 1H, ArH), 7.79 (d, J=8.5Hz, 2H, ArH),
7.74 (s, 1H, ArH), 7.54 (d, J=8.5Hz, 2H, ArH), 7.37 (s, 1H, ArH), 6.61 (dd, J=6.9,1.6Hz,
1H,ArH),2.40(s,3H,CH3)；13C NMR(125MHz,CDCl3)δ146.2,144.4,135.9,133.0,131.8,
127.5,124.8,121.6,115.9,115.2,107.6,21.4.
Claims (7)
1. a kind of synthetic method of 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their, it is characterised in that the synthetic method bag
Include following steps：
(a), will、, iodine and DMAP be placed in mechanico-chemical reaction tank, vibration ball milling is anti-
Should；
(b) after, reaction terminates, product is washed, extract, dry, filtered, filtrate separates after being evaporated through silica gel column chromatography, obtains
To 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their；
Step（a）Described in, R1For H or 4- methyl；
Step（a）Described in, R2For H, 2-Br, 3-Br, 4-Br, 3-NO2、4-NO2、4-SO2Me or 4-OCH3；
Step（a）Described in mechanico-chemical reaction device be that German Lay is speeded mechanico-chemical reaction device；
The structural formula of the 2- phenylimidazoles simultaneously [1,2-a] pyridine compounds and their is：。
2. synthetic method according to claim 1, it is characterised in that the 2- phenylimidazoles simultaneously [1,2-a] pyridines
The structural formula of compound is：, R1For H or 4- methyl；R2For 2-Br, 3-NO2、4-SO2Me、4-OCH3。
3. synthetic method according to claim 1, it is characterised in that step（a）In、, iodine and
The mol ratio of DMAP is 1.2 ~ 1.5:1:1~1.2:1.
4. synthetic method according to claim 1 or 2, it is characterised in that step（a）Described in oscillating reactions condition
For：Frequency of oscillation is 25 ~ 30 Hz.
5. synthetic method according to claim 1 or 2, it is characterised in that step（a）The middle oscillating reactions time is 90 ~ 120
Minute.
6. synthetic method according to claim 1 or 2, it is characterised in that step（b）Described in washing use sulphur
The sodium thiosulfate aqueous solution is washed.
7. synthetic method according to claim 1 or 2, it is characterised in that step（b）The middle drier used is anhydrous sulphur
Sour magnesium.
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| Copper catalyzed tandem oxidative C–H amination/ cyclizations: Direct access to imidazo[1,2-a]pyridines3;Kasiviswanadharaju Pericherla etal;《RSC Advances》;20131231;第3卷;第18925页Table 2 Entry 1-2、5-15 * |
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